Translation of basic research to the field of clinical transplantation is difficult due to the lack of model systems that permit in vivo analysis of a human immune response without putting a patient at risk. The laboratories of Dr. Greiner (my sponsor) and Dr. Shultz (our collaborator) have developed an immunodeficient mouse that supports high levels of human lymphocyte engraftment (termed Hu-PBL-NOD-scid). We propose to establish and validate this model for the study of mechanisms of human immune function and allograft rejection. Our working hypothesis is that Hu-PBL-NOD-scid mice expressing human MHC class 1 and class II molecules will enhance the survival and function of engrafted MHC-matched human T cells. Data i.s been established in two key areas: 1) Genetic stocks of all required human MHC transgenic and murine MHC knockout mice have been assembled. 2) Human skin and islet allograft rejection in Hu-PBL-NOD-scid mice has been documented. Building on these Preliminary Data, the Specific Aims of this proposal are two-fold. Specific Aim #1 is to investigate the mechanisms that underlie the engrafiment, expansion, and survival of human lymphocytes in NOD-scid mice. We propose to test three mechanisms that may act individually or in concert. We will test the hypotheses that expansion and survival of human lymphocytes: A) Results from human anti-mouse MHC class II reactivity; B) Is due to dysregulated homeostasis in the lymphocyte-deficient scid host; C) Requires expression of human MHC class I or class II in the murine hosts for survival. Specific Aim #2 is to test the functional activity of human lymphocytes engrafted in rransgenic NOD-scid mice that express human MHC class I or class II molecules. We propose to validate our Hu-PBL-NOD-scid model as an in vivo model of a functional human immune system for the study allograft rejection. Human MHC transgenic NOD-scid mice will be used to donate allograft targets for engra.fted human lymphocytes. This will validate the functional expression of the human MHC by mouse APCs as a target alloantigen, and validate the ability of human MHC on mouse APCs to present antigen. Our long-term goal is to use the Hu-PBL-NOD-scid model to investigate the mechanisms of human allograft rejection and the modulation of human immune responses by tolerance induction protocols.